1. Field of the Invention
This invention relates to an improved process for synthesizing water-soluble azo compounds on a large scale. More particularly, it relates to an improved azo coupling step in a process for synthesizing soluble polymeric azo compounds. In a preferred embodiment it applies this improvement to the synthesis of polymeric pharmaceuticals.
2. Discussion of the Prior Art and Statement of the Problem to be Solved
The following U.S. patents are commonly assigned herewith and are believed to be representative of references that relate to the synthesis of polymeric azo-linked compounds--U.S. Pat. Nos. 3,920,855 of Dawson et al.; RE30,362 of Gless et al.; and 4,190,176 of Parkinson et al. The first and second references disclose the preparation of polymeric azo dyes while the third reference discloses the preparation of azo-linked polymeric pharmaceutical agents.
The usual procedure for synthesizing an azo group-containing compound is to add a solution of a diazonium salt to an alkaline solution of a coupling agent; for example, ##STR1## Particularly at high pH conditions (pH.gtoreq.12), some of the diazonium groups (cationic) are converted to diazotate groups (anionic). In monomeric reactions, this causes no real problems other than a slightly reduced yield due to the slow reversion of trans-diazotate to the diazonium salt which is needed for the coupling reaction.
When this reaction is conducted with a polymeric diazonium salt, major crosslinking can occur to form a gel; the cause appears to be as follows: ##STR2## If a highly reactive coupling agent, such as a .beta.-naphthol or a pyrazolone, is used the polymeric diazonium salt reacts so quickly with this agent that the conversion from cationic to anionic polymer is quite rapid and usually without observable precipitate formation. However, when a less-reactive coupling agent, such as salicylic acid, is used the polymeric diazonium salt does not react quickly with it. Instead, the cationic diazonium group is slowly converted to the anionic diazotate group. It appears that when the polymer reaches a certain critical ratio of cationic to anionic groups, it precipitates due to this electrostatic attraction (ionic crosslinking). Once the polymer, still bearing many highly reactive diazonium groups, has entered a condensed phase, permanent covalent crosslinks can and do readily form. This problem becomes more acute the higher the molecular weight of the polymer.
Since the reaction rate of the coupling agent cannot be readily increased and the molecular weight of the polymer may be fixed by desired product specifications, the only solutions to this problem are (1) to increase the amount of coupling agent available to the polymeric diazonium salt, and (2) to speed up the conversion of diazonium groups to diazotate groups.
The coupling procedure disclosed in the above-noted representative patents involves dropwise addition of the diazonium salt solution to a well-stirred coupling solution. Even on a small scale, the immediate region of the impacting drop rapidly becomes depleted in both coupling agent and hydroxide ions. At all but a milliliter scale, no amount of conventional magnetic or overhead agitation is adequate to prevent gel formation with less reactive coupling agents.